First-line treatment options for metastatic non-squamous non-small-cell lung cancer (NSCLC) have expanded in the past couple of decades. They have grown from platinum-doublet chemotherapy, to include targeted therapies and combination therapy with monoclonal antibodies targeting programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1).¹Our collective understanding of the molecular mechanisms behind NSCLC has likewise expanded – allowing more subgroups of patients to be identified and the need for treatments targeting their specific genetic make-up to be developed.²

One such subgroup are patients with an activating epidermal growth factor receptor (EGFR) mutation – a group of patients that makes up around 15—20% of Caucasian and up to 50% of the Asian NSCLC non squamous populations, depending on demographics such as smoking status and gender .^3,4 This subgroup have either not been included in previous phase III trials of checkpoint inhibitor combinations or have seen minimal therapeutic benefit.^2,5 In addition, these patients have shorter second line progression-free survival (PFS) after failure of first-line TKI therapy, so this subgroup is one that is in need of more personalised therapies.² To understand the clinical relevance of the data in this space, the limbic spoke with Professor Nick Pavlakis, Consultant Medical Oncologist at North Shore Private Hospital, immediate past President of the Clinical Oncology Society of Australia and current Board Chair of the Thoracic Oncology Group of Australasia (TOGA) . 

“The current paradigm in Australia for patients with sensitising EGFR driven cancer is to treat patients with the tyrosine kinase inhibitor (TKI), osimertinib. The challenge is resistance, particularly in advanced disease and how best to manage it. That’s because resistance is not the same in every patient. You need to consider the patient and the resistance profile to determine the most appropriate course of action. Treatment of isolated brain metastases is different to systemic progression. So too is the treatment of the patient who has been treated for three years and one tumour progresses versus the patient treated for a shorter duration and progression is seen in all places. For the patient with wholescale progression the approach is to find the molecular reason for the failure and see if there is another treatment that matches,” explained Prof. Pavlakis. 

What was the IMpower150 trial? 

IMpower150 was a phase III randomised, open-label study designed to assess the efficacy of the PD-L1 inhibitor atezolizumab in combination with bevacizumab plus carboplatin plus paclitaxel (ABCP) compared to bevacizumab plus carboplatin plus paclitaxel (BCP) in chemotherapy naïve patients with metastatic non-squamous NSCLC. Conducted in over 240 study centres across 26 countries, the IMpower150 trial’s co-primary endpoints were overall survival (OS) and investigator-assessed PFS in intention-to-treat wild-type patients (i.e. patients with EGFR mutations or ALK rearrangements were excluded from this primary analysis).²  

In the primary analysis, the IMpower150 trial showed significant improvements in PFS and OS with ABCP versus BCP in the non-targeted NSCLC population:⁶ 

• Median PFS of 8.3 months in the ABCP arm (n=356) vs 6.8 months in the BCP arm (n=336; HR 0.62; 95% CI 0.52, 0.74; p<0.001) 

• Median OS of 19.2 months in the ABCP arm vs 14.7 months in the BCP arm (HR 0.78; 95% CI 0.64, 0.96; p=0.02) 

Safety was consistent with previous reports for each medicine.⁶  

The first phase III trial to include EGFR-positive patients  

“The IMpower150 trial was the first to give us prospective clinical trial data demonstrating benefit from immunotherapy in patients with sensitising EGFR mutations and ALK rearrangements, with disease progression after TKI therapy. Until then, many patients with EGFR mutations were excluded from previous immunotherapy trials. This trial was a single study, but a positive one. Despite the three-arm design, there was a clear benefit with ABCP compared to BCP,” said Prof. Pavlakis.  

The IMpower150 trial was the first phase III trial to evaluate these combinations of therapy in patients with oncogene-addicted tumours (EGFR and ALK). To be eligible for inclusion, these patients had to have had disease progression or intolerance to treatment with at least one TKI therapy.²  

The subgroup analysis showed an OS and PFS benefit with ABCP (n=34) compared to BCP (n=45) in EGFR-positive patients:² 

• Median PFS was 10.2 months vs 6.9 months for ABCP vs BCP, respectively (HR 0.61; 95% CI 0.36, 1.03) 
• Median OS was not estimable (NE) for ABCP vs 18.7 months for BCP (HR 0.61; 95% CI 0.29, 1.28) 

In the EGFR-positive subgroup, safety was also evaluated. Grade 3-4 adverse events were seen in 65% (21/33) patients in the ABCP group, and 64% (28/44) patients in the BCP group. No patient in in the ABCP group had a grade 5 adverse event, while one patient in the BCP group did.²  

Why ABCP?  

The overall hypothesis of the IMpower150 trial was that combining a checkpoint inhibitor (atezolizumab) with chemotherapy (carboplatin plus paclitaxel) and an anti-VEGF therapy (bevacizumab) would provide additive or synergistic effects, possibly through effects on these processes in the tumour micro-environment.^2,7  

Previous studies of checkpoint inhibitors as monotherapy in EGFR-positive patients have shown no benefit versus standard-of-care chemotherapy in the second-line setting. It is thought that the addition of bevacizumab may promote T-cell tumour infiltration, enhancing tumour sensitivity to checkpoint inhibitors – which may explain the PFS, and OS benefit seen in EGFR-positive ABCP treated patients compared to BCP treated patients in the IMpower150 trial.² 

TECENTRIQ (atezolizumab) approved Australian indication and PBS availability 

TECENTRIQ plus bevacizumab plus platinum doublet chemotherapy is the only immunotherapy-chemotherapy combination PBS funded for EGFR-positive metastatic non-squamous NSCLC after failure of appropriate TKIs.⁸ 

TECENTRIQ is approved for use by the Therapeutic Goods Administration in combination with bevacizumab, paclitaxel and carboplatin for the first-line treatment of adult patients with metastatic non-squamous NSCLC. In patients with EGFR mutant or ALK-positive NSCLC, TECENTRIQ, in combination with bevacizumab, paclitaxel and carboplatin, is indicated only after failure of appropriate targeted therapies.⁹ 

What do these data mean for clinicians? 

“IMpower150 is the only randomised, controlled trial to show benefit in the molecularly defined subgroups, defined as having EGFR mutations or ALK gene arrangements progressed on prior TKI therapy. However, there are some important considerations for clinicians taking this regimen into the clinic. The chemotherapy backbone is not commonly used at the doses used in this study. It’s important to consider the fitness of the patient and know from our experience in clinic that lower doses of chemotherapy may be appropriate or even substituting pemetrexed for paclitaxel,” explained Prof. Pavlakis. He continued to explain how with the IMpower150 regimen it’s relatively straightforward to assign side effect profiles according to the drugs and manage accordingly. “Bevacizumab may not be familiar to all, but we are certainly familiar with the chemotherapy and immunotherapy profiles.” 

In summarising, Prof. Pavlakis reiterated the importance of taking a personalised approach. “Gather as much information as you can to guide the treatment course as we now have more data to guide treatment options for patients with progression on TKIs.” 

[Footnote]

ALK=anaplastic lymphoma kinase; CI=confidence interval; HR=hazard ratio; TKI=tyrosine kinase inhibitor.

Disclosure

This article was sponsored by Roche. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review the Tecentriq product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.

References

1. Peters S, et al. Ann Oncology 2019;30: 884–896.
2. Reck M, et al.  2019 Lancet Respir Med 2019;7: 387–401.
3. Harrison PT, et al. Semin Cancer Biol 2020;61:167-179.
4. Qu J, et al. Cancer Manag Res 2020;12:6493-6509
5. Lee CK, et al. J Thorac Oncol 2017;12(2):403-407.
6. Socinski MA, et al. N Engl J Med 2018;378:2288-301.
7. Morrisey KM, et al. Clin Transl Sci. 2016; 9(2): 89–104.
8. Pharmaceutical Benefits Scheme, Atezolizumab. Available from: www.pbs.gov.au (accessed November 2021).
9. TECENTRIQ (atezolizumab) Approved Product Information.